Spero Therapeutics Announces Fourth Quarter and Full-Year 2019 Operating Results and Provides Pipeline Update 2020 catalysts include tebipenem HBr pivotal Phase 3 top-line cUTI data in 3Q20 and SPR720 Phase 2a NTM trial

Spero Therapeutics Announces Fourth Quarter and Full-Year 2019 Operating Results and Provides Pipeline Update

2020 catalysts include tebipenem HBr pivotal Phase 3 top-line cUTI data in 3Q20 and SPR720 Phase 2a NTM trial

CAMBRIDGE, Mass., March 16, 2020 Spero Therapeutics, Inc. (Nasdaq:SPRO), a multi-asset clinical-stage biopharmaceutical

company focused on identifying, developing and commercializing treatments in high unmet need areas involving multi-drug resistant bacterial infections and rare diseases, today announced financial results for the fourth quarter and full-year ended

December 31, 2019 and provided a pipeline update.

In 2019 and continuing into 2020, we have made significant clinical progress with positive

clinical data reported for all of our pipeline programs, all of which are designed to address serious unmet needs and to treat multi-drug resistant infections, said Ankit Mahadevia, M.D., Chief Executive Officer of Spero Therapeutics. We

have a solid cash position heading into 2020 bolstered by proceeds from our $30 million rights offering that closed in early March 2020, and we look forward to an eventful 2020 that includes top-line data from

our pivotal Phase 3 clinical trial of tebipenem HBr in complicated urinary tract infections (cUTI) expected in the third quarter of 2020.

Clinical Highlights and Upcoming Milestones

Spero s lead product candidate, tebipenem HBr, has the potential to be the first oral carbapenem antibiotic approved for use in adults to treat MDR

Gram-negative infections. Spero s pivotal Phase 3 clinical trial of tebipenem HBr for the treatment of cUTI, ADAPT-PO, is currently enrolling patients. The ADAPT-PO

trial compares an all oral regimen of tebipenem HBr with an existing standard of care intravenous (IV) antibiotic, ertapenem, in approximately 1,200 patients with cUTI or acute pyelonephritis, randomized 1:1 in each arm. In October 2019, an

independent review committee analyzed interim pharmacokinetic (PK) data from the first 33 patients dosed with tebipenem HBr and recommended the continuation of the trial using the protocol-defined dose without modification. Spero continues to expect

to report top-line data from the ADAPT-PO trial in the third quarter of 2020. To support continued clinical development of tebipenem HBr, in February 2020 the Biomedical

Advanced Research and Development Authority (BARDA) exercised a $15.9 million option under its existing contract with Spero, bringing the total committed funding under the award to $44.0 million in

non-dilutive funding, inclusive of $10.0 million in funding from the Defense Threat Reduction Agency (DTRA).

SPR720 is an orally administered antimicrobial

agent being developed by Spero for the treatment of non-tuberculous mycobacterial (NTM) disease, a rare orphan disease, as well as other infections, including Mycobacterium tuberculosis. In December

2019, Spero reported positive preliminary results from its Phase 1 clinical trial of SPR720 in healthy volunteers indicating that SPR720 was generally well-tolerated at doses up to 1000 mg over the maximum studied duration of 14 days, with a PK

profile that Spero believes supports its further development as an oral agent for the treatment of NTM pulmonary disease. The Phase 1 clinical trial was designed as a double-blind, placebo-controlled clinical trial to assess the safety, tolerability

and pharmacokinetics of SPR720 at single and multiple ascending doses in healthy volunteers. In March 2020, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation for SPR720, a designation that is given to drugs intended to

treat a rare disease or condition that affects fewer than 200,000 persons in the United States. Spero expects to present final data from the SPR720 Phase 1 clinical trial at a medical conference in 2020. Spero plans to meet with the FDA in the first

half of 2020, submit an investigational new drug (IND) application for SPR720 to the FDA in the second half of 2020, and subject to FDA acceptance of the IND, initiate a dose-ranging Phase 2a clinical trial evaluating SPR720 in patients with NTM

disease due to Mycobacterium avium complex (MAC) in the second half of 2020.

SPR206 is an IV-administered product candidate being developed as an innovative option to treat MDR Gram-negative

bacterial infections. In January 2020, Spero reported positive preliminary Phase 1 clinical trial data for SPR206 in healthy volunteers demonstrating that SPR206 was well-tolerated at doses likely to be within a therapeutic range for MDR

Gram-negative bacterial infections. The Phase 1 clinical trial was designed as a double-blind, placebo-controlled, single and multiple ascending dose, multi-cohort study in healthy volunteers. Spero expects to present final data from the

Phase 1 clinical trial in the first half of 2020. In conjunction with Everest Medicines, and through its grant from the U.S. Department of Defense awarded in July 2019, Spero plans to conduct a Phase 1 bronchoalveolar

lavage (BAL) clinical trial assessing the penetration of SPR206 into the pulmonary compartment in the second half of 2020 and initiate a renal impairment study of SPR206.

Fourth Quarter and Full-Year 2019 Financial Results

Spero reported a net loss for the fourth quarter and year ended December 31, 2019 of $25.2 million and $60.9 million, or $1.32 and $3.35 per

common share, respectively. Net loss for the fourth quarter and year ended December 31, 2018 was $10.6 million and $41.7 million, or $0.60 and $2.60 per common share, respectively.

Total revenue for the fourth quarter and year ended December 31, 2019 was $3.6 million and $18.1 million, respectively, and was comprised of

reimbursement for all of Spero s pipeline programs. Grant revenue for the year ended December 31, 2019 was $14.2 million higher than the same period of 2018 due to greater funding for tebipenem HBr received under the BARDA contract

awarded in July 2019 that allows for reimbursement for prequalified expenses.

Research and development expenses for the fourth quarter 2019 of

$25.7 million were higher than $9.1 million for the same period of 2018 due to higher direct clinical trial expense primarily from the ongoing ADAPT-PO Phase 3 trial that began enrolling patients in

the first quarter of 2019. Research and development expenses for the year ended December 31, 2019 were $65.8 million compared to $33.9 million for the year ended December 31, 2018, with increased expenses in 2019 versus 2018 due

to greater spend on tebipenem HBr and as well as SPR720 program expenses, partially offset by lower spend on Spero s Potentiator Platform product candidates. Spero expects that its research and development expenses will increase in 2020 due to

greater planned spend associated with the ADAPT-PO Phase 3 clinical trial and preparation of a potential New Drug Application (NDA) filing for tebipenem HBr, as well as the initiation of a Phase 2a clinical

trial for SPR720 in NTM, along with increased research and development personnel to support the ongoing and planned programs.

General and administrative

expenses for the fourth quarter 2019 of $3.8 million were slightly higher than $3.6 million for the same period of 2018, primarily due to increased headcount. General and administrative expenses for the year ended December 31, 2019

were $15.6 million compared to $12.9 million for the year ended December 31, 2018, with the increased expenses in 2019 versus 2018 primarily due to an increase in headcount, professional fees and facility-related expenses. Spero

expects general and administrative expenses to increase in 2020 due to additional headcount and professional fees required to support tebipenem HBr as it advances towards regulatory approval as well as increased facility-related expenses to support

the expanding headcount.

As of December 31, 2019, Spero had cash, cash equivalents and marketable securities of $82.0 million. Subsequent to year-end 2019, on March 5, 2020 Spero announced the closing of its rights offering for $30 million in gross proceeds. Spero believes that its existing cash, cash equivalents and marketable securities as

well as proceeds from the completed rights offering, together with committed funding from our BARDA contract and other non-dilutive funding commitments, will enable funding of its operating expenses and

capital expenditure requirements into the first quarter of 2021, including through the filing of an NDA for tebipenem HBr.

Upcoming Scientific and

Investor Presentations

Spero Therapeutics, Inc. is a multi-asset, clinical-stage biopharmaceutical company focused on identifying, developing and commercializing novel treatments for

multidrug-resistant (MDR) bacterial infections and rare diseases.

Spero s lead product candidate, tebipenem HBr (tebipenem pivoxil hydrobromide;

formerly SPR994), is designed to be the first oral carbapenem-class antibiotic for use in adults to treat MDR Gram-negative infections.

advancing SPR720, its novel oral therapy product candidate designed for the treatment of rare, orphan disease caused by pulmonary non-tuberculous mycobacterial (NTM) infections.

Spero also has a platform technology known as its Potentiator Platform that includes an IV-administered product

candidate, SPR206, being developed to treat MDR Gram-negative infections in the hospital setting.

For more information, visit

https://sperotherapeutics.com.

Forward Looking Statements

This press release may contain forward-looking statements. These statements include, but are not limited to, statements about Spero s expectation that

positive results from a single pivotal Phase 3 clinical trial of tebipenem HBr and ancillary supportive studies to be conducted in parallel with the Phase 3 trial will support the approval of tebipenem HBr; the design, initiation, timing, progress

and results of Spero s preclinical studies and clinical trials and its research and development programs, including the timing of Spero s regulatory meeting with the FDA regarding SPR720, the timing of Spero s IND submission

with the FDA regarding SPR720, the commencement of Spero s planned Phase 2a clinical trial of SPR720 and the commencement of Spero s planned Phase 1 bronchoalveolar lavage (BAL) clinical trial assessing the penetration of SPR206

into the pulmonary compartment; management s assessment of the results of such preclinical studies and clinical trials; the timing of clinical data, including the availability of pharmacokinetic data from the

lead-in cohort in the Phase 3 clinical trial of tebipenem HBr, final data from the Phase 1 clinical trial of SPR720 and final data from the Phase 1 clinical trial of SPR206; and Spero s cash forecast and

anticipated expenses, anticipated payments under Spero s agreement with Everest Medicines, potential payments under Spero s agreement with BARDA, the sufficiency of its cash resources and the availability of additional non-dilutive funding from governmental agencies beyond any initially funded awards. In some cases, forward-looking statements can be identified by terms such as may, will, should,

expect, plan, aim, anticipate, could, intent, target, project, contemplate, believe, estimate, predict,

potential or continue or the negative of these terms or other similar expressions. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors,

including whether the FDA will accept a single pivotal study for approval of tebipenem HBr; whether results obtained in preclinical studies and clinical trials will be indicative of results obtained in future clinical trials; whether

Spero s product candidates will advance through the preclinical development and clinical trial process on a timely basis, or at all, taking into account the effects of possible regulatory delays, slower than anticipated patient enrollment,

manufacturing challenges, clinical trial design and clinical outcomes; whether the results of such trials will warrant submission for approval from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies; whether

Spero will satisfy all of the pre-conditions to receipt of the development milestone payment under its agreement with Everest Medicines; whether BARDA elects to exercise its second option under Spero s

agreement with BARDA; whether Spero s cash resources will be sufficient to fund its continuing operations for the periods and/or trials anticipated; whether Spero s clinical and preclinical development programs are delayed or disrupted due

to the coronavirus; and other factors discussed in the Risk Factors set forth in filings that Spero periodically makes with the U.S. Securities and Exchange Commission. The forward-looking statements included in this press release

represent Spero s views as of the date of this press release. Spero anticipates that subsequent events and developments will cause its views to change. However, while Spero may elect to update these forward-looking statements at some point in

the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Spero s views as of any date subsequent to the date of this press release.

Spero Investor and Media Contact:

Senior Director, Investor Relations

Spero Therapeutics, Inc.

Condensed Consolidated Balance Sheet Data

Condensed Consolidated Statements of Operations

(in thousands, except share and per share data)